DNA ploidy in curettage specimens identifies high-risk patients and lymph node metastasis in endometrial cancer.

BACKGROUND: Preoperative risk stratification is essential in tailoring endometrial cancer treatment, and biomarkers predicting lymph node metastasis and aggressive disease are aspired in clinical practice. DNA ploidy assessment in hysterectomy specimens is a well-established prognostic marker. DNA ploidy assessment in preoperative curettage specimens is less studied, and in particular in relation to the occurrence of lymph node metastasis. METHODS: Curettage image cytometry DNA ploidy in relation to established clinicopathological variables and outcome was investigated in 785 endometrial carcinoma patients prospectively included in the MoMaTEC multicentre trial. RESULTS: Diploid curettage status was found in 72.0%, whereas 28.0% were non-diploid. Non-diploid status significantly correlated with traditional aggressive postoperative clinicopathological features, and was an independent predictor of lymph node metastasis among FIGO stage I-III patients in multivariate analysis (OR 1.94, P=0.033). Non-diploid status was related to shorter disease-specific survival (5-year DSS of 74.4% vs 88.8% for diploid curettage, P<0.001). When stratifying by FIGO stage and lymph node status, the prognostic effect remained. However, in multivariate regression analysis, preoperative histological risk classification was a stronger predictor of DSS than DNA ploidy. CONCLUSIONS: Non-diploid curettage is significantly associated with aggressive clinicopathological phenotype, lymph node metastasis, and poor survival in endometrial cancer. The prognostic effect was also observed among subgroups with (presumably) less aggressive traits, such as low FIGO stage and negative lymph node status. Our results indicate curettage DNA ploidy as a possible supplement to existing parameters used to tailor surgical treatment.

A discordant histological risk classification in preoperative and operative biopsy in endometrial cancer is reflected in metastatic risk and prognosis.

INTRODUCTION: In endometrial cancer, tissue for histological evaluation is obtained preoperatively (endometrial biopsy) and operatively (hysterectomy specimen). We investigated if a discordant risk classification based on preoperative and operative biopsy is reflected in metastatic risk and prognosis. PATIENTS AND METHODS: One thousand three hundred and seventy-four patients were prospectively included in a multicentre setting (Molecular Markers for Treatment of Endometrial Cancer (MoMaTEC) study). Preoperative and operative specimens were classified as high risk if non-endometrioid histology or endometrioid grade 3; otherwise low risk. Disease specific survival differences were calculated by means of Kaplan-Meier and Cox proportional hazard models. RESULTS: Discordant risk was found in 207 (16%) cases. Lymph node metastases were detected in 7% and 23% of patients with concordant low and high risk respectively versus 14% and 20% in the discordant groups (p<0.001). Five-year disease specific survival in the discordant groups proved intermediate (75-80%) to concordant low (94%) or high (58%) risk. Both operative and preoperative biopsy high-risk results have independent prognostic impact on disease specific survival with adjusted hazard ratios of 2.4 (95% confidence interval (95% CI) 1.5-3.9) and 2.1 (95% CI 1.3-3.2) respectively by Cox analysis. CONCLUSIONS: Discordant risk in preoperative biopsy and hysterectomy identifies an intermediate group with respect to disease spread and prognosis. Preoperative biopsy results remain important also with the hysterectomy histology available.

Polyploid formation pathways have an impact on genetic rearrangements in resynthesized Brassica napus.

• Polyploids can be produced by the union of unreduced gametes or through somatic doubling of F(1) interspecific hybrids. The first route is suspected to produce allopolyploid species under natural conditions, whereas experimental data have only been thoroughly gathered for the latter. • We analyzed the meiotic behavior of an F(1) interspecific hybrid (by crossing Brassica oleracea and B.rapa, progenitors of B.napus) and the extent to which recombined homoeologous chromosomes were transmitted to its progeny. These results were then compared with results obtained for a plant generated by somatic doubling of this F1 hybrid (CD.S0) and an amphidiploid (UG.S0) formed via a pathway involving unreduced gametes; we studied the impact of this method of polyploid formation on subsequent generations. • This study revealed that meiosis of the F1 interspecific hybrid generated more gametes with recombined chromosomes than did meiosis of the plant produced by somatic doubling, although the size of these translocations was smaller. In the progeny of the UG.S0 plant, there was an unexpected increase in the frequency at which the C1 chromosome was replaced by the A1 chromosome. • We conclude that polyploid formation pathways differ in their genetic outcome. Our study opens up perspectives for the understanding of polyploid origins.

The first meiosis of resynthesized Brassica napus, a genome blender.

Polyploidy promotes the restructuring of merged genomes within initial generations of resynthesized Brassica napus, possibly caused by homoeologous recombination at meiosis. However, little is known about the impact of the first confrontation of two genomes at the first meiosis which could lead to genome exchanges in progeny. Here, we assessed the role of the first meiosis in the genome instability of synthetic B. napus. We used three different newly resynthesized B. napus plants and established meiotic pairing frequencies for the A and C genomes. We genotyped the three corresponding progenies in a cross to a natural B. napus on the two homoeologous A1 and C1 chromosomes. Pairing at meiosis in a set of progenies with various rearrangements was scored. Here, we confirmed that the very first meiosis of resynthesized plants of B. napus acts as a genome blender, with many of the meiotic-driven genetic changes transmitted to the progenies, in proportions that depend significantly on the cytoplasm background inherited from the progenitors. We conclude that the first meiosis generates rearrangements on both genomes and promotes subsequent restructuring in further generations. Our study advances the knowledge on the timing of genetic changes and the mechanisms that may bias their transmission.

Combined diphtheria-tetanus-pertussis vaccine for tetanus-prone wound management in adults.

INTRODUCTION: Booster vaccination against tetanus, diphtheria and pertussis is recommended throughout life. Adults are difficult to reach and vaccination coverage in this group is often inadequate. The use of a reduced-antigen content combined diphtheria-tetanus-acellular pertussis ('adult' dTpa) vaccine for tetanus prophylaxis in emergency room wound management provides an opportunity to boost immunity against three infections simultaneously, thereby optimizing the efficiency of medical interventions with adults assessed. METHODS: A single-blind, randomized, controlled study of 320 healthy adults, the anti-tetanus antibody response within 10 days following vaccination with Boostrix (reduced-antigen diphtheria-tetanus-acellular pertussis). RESULTS: The anti-tetanus antibody response to the reduced-antigen diptheria-tetanus-acellular pertussis vaccine was equivalent to Tetavax, a licensed monovalent tetanus-toxoid vaccine. CONCLUSION: The use of diphtheria-tetanus-acellular pertussis is a safe and effective way to provide vaccination to adults against three diseases during emergency room visits for wound management.

Combined reduced-antigen-content diphtheria-tetanus-acellular pertussis and polio vaccine (dTpa-IPV) for booster vaccination of adults.

Many countries recommend diphtheria, tetanus and/or poliomyelitis boosters in adolescents or adults and the need for pertussis booster vaccination beyond childhood is increasingly recognized. A new combined reduced-antigen-content dTpa-IPV vaccine provides booster vaccination against all four diseases in one single injection. The immunogenicity and safety of the dTpa-IPV vaccine was compared to that of licensed dTpa+IPV or Td-IPV vaccines in 806 adolescents >14 years of age and adults with a heterogeneous vaccination history. The dTpa-IPV vaccine was immunogenic and well tolerated. No clinically significant differences were observed between groups. Anti-tetanus antibody kinetics indicated that each of the vaccines could be used for tetanus prophylaxis in acute wound management. For all vaccines, the lowest post-vaccination antibody concentrations were observed in subjects >40 years of age, those seronegative prior to vaccination and those subjects whose last vaccination was > or =20 years ago. In conclusion, dTpa-IPV vaccination of subjects over 14 years of age was as immunogenic and well tolerated as the licensed dTpa+IPV or Td-IPV vaccines. Vaccination coverage of adults is poor and the use of combined vaccines such as dTpa-IPV during vaccination visits, or for wound management, maximizes opportunities for boosting in these difficult to reach age groups.

High levels of antibody in adults three years after vaccination with a reduced antigen content diphtheria-tetanus-acellular pertussis vaccine.

There is increasing interest in prevention of pertussis in adults by vaccination, but little is known about the duration of the antibody response to pertussis, diphtheria or tetanus in reduced antigen content vaccines formulated for adult use. Follow-up of a clinical trial including 550 adults comparing responses to reduced antigen content diphtheria-tetanus-acellular pertussis (dTpa) vaccine, or a licensed Td vaccine, provided the opportunity to evaluate this. Blood samples were collected at 0, 1, 12, 24 and 36 months following vaccination; of the original cohort of 550, 387 subjects (dTpa group N=310, Td+pa group N=77) were tested at month 36. Following a decrease in antibody levels against all vaccine antigens between one and 24 months following vaccination, levels stabilized during the third year, remaining higher at 36 months than pre-vaccination for all vaccine antigens. In particular, more than 90% of subjects remained seropositive for pertussis toxin and pertactin antibodies at 36 months after vaccination, suggesting ongoing protection against pertussis. Adult-formulated dTpa vaccines could replace Td for routine booster vaccination of older individuals.

Biased distribution of chromosomal breakpoints involving the MLL gene in infants versus children and adults with t(4;11) ALL.

Derivative chromosomes of 40 patients diagnosed with t(4;11) acute lymphoblastic leukemia (ALL) were analysed on the genomic DNA level. Chromosomal breakpoints were identified in most cases within the known breakpoint cluster regions of the involved MLL and AF4 genes. Due to our current knowledge of the primary DNA sequences of both breakpoint cluster regions, specific features were identified at the chromosomal fusion sites, including deletions, inversions and duplications of parental DNA sequences. After separation of all t(4;11) leukemia patients into two age classes (below and above 1 year of age), the analysis of chromosomal fusion sites revealed significant differences in the distribution of chromosomal breakpoints and led to the definition of two hotspot areas within the MLL breakpoint cluster region. This may point to the possibility of different age-linked mechanisms that were leading to t(4;11) chromosomal translocations.